Project Summary This is a request to the NIH for an Investigator-Initiated Research Project Grant (R01) for Bruce K. Tan, MD, MS, Assistant Professor of Otolaryngology at Northwestern University. The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Unfortunately, many patients with chronic rhinosinusitis (CRS) suffer from extended periods of smell loss despite medical and surgical treatment. We further find that patients with type 2 inflammation of the nasal mucosa are more frequently and severely affected by smell loss before and after sinus surgery. CRS patients with type 2 inflammation are also more likely to experience recurrence of their symptoms and require repeated surgery. The Principal Investigator is a surgeon-scientist whose clinical interests focus on CRS patients but has completed extensive mentored training in mucosal immunity. This proposal seeks to translate a recent novel discovery in our laboratory that found that airway epithelial cell responses to IL-4 and -13, critical type 2 cytokines causing the most severe forms of chronic sinusitis, require action of an ion pump called the non-gastric H+/K+ATPase. Specific experiments will: (1) evaluate mechanisms by which the non-gastric H+/K+ATPase causes airway inflammation using drug inhibitors and genetic knockout cell lines; (2) evaluate how to use smell loss to accurately identify patients with active type 2 inflammation after sinus surgery; and (3) perform clinical studies to find out how to effectively use proton pump inhibitors to reduce airway eosinophilic inflammation and test whether they can reduce type 2 inflammation and improve smell function in patients with CRS. If successful, these studies will firmly establish a novel mechanism that disrupts the airway barrier in type 2 inflammatory conditions. Additionally, the results of this study may identify less invasive methods to identify type 2 inflammation in the nasal airway. Finally, the clinical studies may discover new drugs to treat persistent type 2 inflammation and smell loss in patients after sinus surgery- problems for which there are currently no effective medical treatments.